Chronic obstructive pulmonary disease (COPD), a disease characterized by inflammation, cell death and extensive lung tissue remodeling, is an increasingly important public health concern in the United States and worldwide (Lee et al. 2009; Maclay et al. 2009). COPD is the fourth leading cause of death worldwide and the World Health Organization predicts that by the year 2030 COPD will become the third leading cause of death (Godtfredsen et al. 2008). It is estimated that 170,000 Americans die of COPD annually and direct and indirect expenditures on COPD exceed 48 billion dollars (Mannino et al. 2009). While research efforts have led to decreases in the prevalence of most diseases, COPD is on the rise in first world countries (Lee et al. 2009; Maclay et al. 2009).
Although the molecular mechanisms underlying development of COPD remain incompletely understood, heightened expression of pro-inflammatory molecules, lung cell death and tissue remodeling are believed to play critical roles. (Postma and Timens, 2006; Salazar and Herrera, 2011; Westergren-Thorsson et al., 2010) The intensity of inflammatory responses and alterations in cell behavior reflect both the activation state of signaling proteins upstream of genes of interest and signal-induced assembly of nuclear chromatin complexes that support the formation of mRNA. Specifically, in COPD, alterations in gene expression result both from activation of key transcription factors and from epigenetic changes which affect chromatin remodeling (e.g., altered histone acetylation). (Macnee, 2007; Rajendrasozhan et al., 2009)
Nuclear chromatin which includes the several histones is the cell scaffolding which promotes the interaction between DNA and the transcription factors which affect gene expression (Lamond and Earnshaw 1998). Post-translational modification of histones affects gene regulation (Taverna et al., 2007; Voigt and Reinberg, 2011; Wood et al., 2009) In fact, changes in histone acetylation induced by reductions in histone deacetylase (HDAC) expression contribute to the heightened inflammatory state present in the lung in COPD (Barnes, 2009a, b; Bhavsar et al., 2008). Of interest, however, histones also exert diverse functions when present extracellularly (Papayannopoulos and Zychlinsky, 2009; Wiesner and Vilcinskas, 2010) For example, histones are potent anti-microbials, more potent than conventional antibiotics (Kawasaki and Iwamuro, 2008; Papayannopoulos and Zychlinsky, 2009; Wiesner and Vilcinskas 2010) Moreover, while histones are not generally believed to be noxious, they induce lung inflammation and damage when present in the circulation and are cytotoxic to human lung cells when present in the extracellular space. (Xu et al., 2009)
Chromatin remodeling and epigenetic changes determine gene transcription by affecting transcription factor and RNA polymerase binding to DNA (Weake and Workman, 2010; Yu and Waters, 2005). In particular, post-translational modification of amino acids in core histones including lysine hyper acetylation induces inflammatory gene expression in COPD (Barnes, 2009a, c; Bhavsar et al., 2008). However, the nature of other post-translational modifications in COPD and the discrete amino acids involved remain poorly understood.
What is needed are methods of diagnosing and staging COPD, as well as methods of treating COPD.